Lyme disease is the most prevalent tick-borne disease in the northern hemisphere with many endemic areas in Europe and around the world. The disease is a multi-system spirochetosis with dermatologic, neurologic and rheumatological manifestations. Central to the disease process, in the absence of a demonstrated toxin, is the interaction between the microorganism and host cells. Cytoadhesive receptors expressed on cell surfaces are essential for cell-cell interaction and adhesion to the extracellular matrix. Many microorganisms have evolved the ability to use these surface receptors, called integrins, to bind and then to invade host cells. A broadly applicable method has been developed in which scanning electron microscopy (SEM) is used to assess this binding potential under carefully controlled experimental conditions. The rapid assay uses genetically engineered cytoadhesive molecules and site specific competitive inhibitors to characterize the interaction of Borrelia burgdorferi, the Lyme disease spirochete, with specific cell surface receptors. The specific use of the fibronectin, but not vitronectin or laminin cellular binding receptors, has been demonstrated using this new assay. Gentle disruption and washing of bound spirochetes with N-lauroylsarcosine followed by detergent elution and polyacrylamide gel electrophoresis of bound polypeptides revealed a unique subset of components. Borrelial major outer surface protein A (OspA) was prominent among them. Pretreatment of fibronectin coated membranes with recombinant OspA protein appeared to block binding of the spirochetes as efficiently as did the specific RGD disintegrin molecule, flavoridin.